Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma

-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with -deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with -deficient tumors that experienced short overall survival (=3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one -deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with -deficient HGSC with a more elevated HRD score survived significantly longer. Patients with -deficient HGSC and loss of survived twice as long as those without loss, whereas or amplification defined -deficient HGSC with exceptionally short survival. -deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline variants (g pv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in g pv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in -deficient HGSC.